Antibody-based lung fibrosis therapy gets a redesign

Australian biotech AdAlta has announced major improvements to the design of its preclinical ‘i-body’ therapy for lung fibrosis, AD-114, which have significantly enhanced the drug’s potency and extended its half-life.

The molecule known as AD-114 is designed to mimic the shape of the antigen-binding domain of shark antibodies and their key stability features. It can carry out the functional role of recognising and binding to other molecules/antigens, including disease targets, to produce a therapeutic effect. Preclinical research released in February found that AD-114 selectively targets and binds to CXCR4, a protein expressed at higher levels in patients with lung fibrosis.

The improved version of the molecule, AD-214, contains two AD-114 i-body molecules at its front end. This increases its ability to bind to its human target, CXCR4, where it exerts its therapeutic effect. The addition of an Fc fragment (the tail region of a traditional monoclonal antibody) meanwhile extends AD-214’s half-life — the duration of time in which it will stay in the body.

“An increased half-life results in significantly less frequent dosing and therefore a more desirable and acceptable outcome for patients, leading to greater drug compliance,” said AdAlta CEO Sam Cobb. Less frequent dosing is additionally expected to help reduce the costs of goods, as is the straightforward manufacturing method for the Fc-Fusion proteins.

Cobb said the company will progress AD-214 into a Phase I clinical trial in the second half of 2019. Accordingly, the company will prioritise development of AD-214 and halt further expenditure on manufacturing the current AD-114 molecule.

“AD-214 will widen the commercial interest when we progress our partnering discussions,” said Cobb. “Although the redesign of AD-114 into the new Fc-Fusion molecule AD-214 delays us from entering human clinical trials by around 12 months, AdAlta believes the timeline associated with this new molecule is more than offset by its broader clinical utility in a wider range of fibrotic diseases outside of idiopathic pulmonary fibrosis.”

AdAlta Non-Executive Director Dr Robert Peach has a long history in the development of commercially available biologic drugs, including the Fc-Fusion drug blockbuster Orencia. He commented, “The data on AdAlta’s CXCR4 i-body antagonist is extremely encouraging for the treatment of multiple fibrotic diseases, including NASH, and age-related macular degeneration.

“We have been able to leverage all the work done to date on AD-114 in the development of AD-214. This means we can make use of our existing strong data package and retain orphan drug status for treatment of idiopathic pulmonary fibrosis.

“We expect AD-214 will deliver increased commercial and therapeutic benefits in multiple fibrotic conditions, combined with the strong commercial precedent of existing mainstream drugs developed using the Fc-Fusion route [which] reinforces the validity of this approach.”

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